Synthesis and in vivo studies of [C-11]N-methylepibatidine: comparison of the stereoisomers

Patt, J. T.; Spang, Jörg E; Westera, G.; Buck, Alfred; Schubiger, P. August

doi:10.1016/s0969-8051(98)00084-5

Cited by 29 publications

(24 citation statements)

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“…While the (+)-N-methyl-enantiomer was 15-and 30-fold less sensitive than (+)-epibatine on α4β2 and α3β4, respectively; the (-)-N-methyl-enantiomer was no different than (-)epibatidine on α4β2 and α3β4. The reported toxicity of N-methylepibatidine, however, is too high to ensure a safety margin for human studies [77,128]. Similar findings were reported during the evaluation of stereoisomers of [ 11 CH 3 ]N-methylhomoepibatidine in rats and pigs, where despite appropiate kinetic profiles allowing quantification, toxicity concerns preclude their use in humans [129].…”

Section: A New Imaging Studies With Previously Developed Radiolabelesupporting

confidence: 56%

“…14) [128] in rats showed a different binding pattern for the two enantiomers: The (-) enantiomer showed slower brain kinetics, higher brain uptake, and binding mainly to the brain, while the (+) enantiomer displayed lower uptake, faster kinetics and binding to the eyes as well. Although epibatidine itself does not show a remarkable stereoselectivity, the N-methyl derivative displayed different binding profiles for the two enantiomers, in a fashion similar to that for nicotine.…”

Section: A New Imaging Studies With Previously Developed Radiolabelementioning

confidence: 97%

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The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Horti¹,

Villemagne²

2006

CPD

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Neuronal nicotinic acetylcholine receptors (nAChRs), ubiquitously distributed in the human brain, are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of Alzheimer's and Parkinson's diseases, Tourette's syndrome, epilepsy, schizophrenia, depression, and anxiety, as well as being particularly affected in tobacco dependence/withdrawal. In the past two decades, researchers have developed an extensive series of radioligands for the assessment of nAChRs in vivo through emission tomography, PET and SPECT. Several radioligands, derivatives of A-85380: 2-[(18)F]FA, 6-[(18)F]FA and 5-[(123)I]IA, are now being employed for the evaluation of nAChR in humans with PET and SPECT. Displaying better imaging properties than (11)C-nicotine and a better toxicity profile than epibatidine analogs, they have allowed quantification of thalamic nAChR in the human brain. Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio. Current research efforts on the part of PET/SPECT radiochemists, therefore, have focused on development of new, highly specific and highly selective nAChR radioligands with improved brain kinetics that are able to localize high-affinity nAChRs in vivo. Key examples of new PET/SPECT ligands that are derived from several different structural classes are discussed along with a review of their chemical as well as their in vitro and/or in vivo properties. In particular, new PET nAChR radioligands will be examined that either present faster brain kinetics allowing simple and reliable quantification approaches or higher binding potentials suitable for the evaluation of extrathalamic nAChR.

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Section: A New Imaging Studies With Previously Developed Radiolabelesupporting

confidence: 56%

Section: A New Imaging Studies With Previously Developed Radiolabelementioning

confidence: 97%

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Horti¹,

Villemagne²

2006

CPD

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“…injection [119] . These values are about ten-fold higher than those reported for N-methylepibatidine [120] and fl uoro-norchloroepibatidine [121] .…”

Section: Fig 2 Key Molecules For Development Of New Pet Radiotracercontrasting

confidence: 59%

“…injection [119] . These values are about ten-fold higher than those reported for N-methylepibatidine [120] and fl uoro-norchloroepibatidine [121] .Regarding α7 nAChRs, many drug companies are developing receptor agonists and/or positive allosteric modulators for the treatment of schizophrenia and dementia [97] . Recently, NS10743, developed by NeuroSearch A/S (Ballerup, Denmark), has been characterized as a lead structure for PET radiotracer development.…”

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confidence: 99%

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including geneticallyengineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.Keywords: Alzheimer's disease; autoradiography; blood-brain barrier; brain tumor; cholinergic system; kinetic modeling; metabolism; molecular imaging; neurodegeneration; positron emission tomography; precursor; psychiatric disorder; radiotracer; sigma receptor ·Review· IntroductionPositron emission tomography (PET) is an in vivo molecular imaging tool widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. Positron-emitting radionuclide-labeled substances allow the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems by highly sensitive coincidence-detection [1] . This is based on 511 keV photons (gamma radiation) originating from positronelectron annihilation. PET differs in that aspect from other modalities such as single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound. Because of their high sensitivity (~10 -9 to 10 -12 M) PET and SPECT offer advantages over the other methods. Therefore, in the past, they were the only modalities that allowed noninvasive imaging of biochemical receptor sites. Nowadays, the other imaging modalities compete in that aspect although precise absolute quantitation in terms of biochemical parameters has not been achieved yet. fusion accuracy, provides an advanced diagnostic tool and research platform [2,3] .PET and SPECT use biomolecules as probes, labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. According to the concept developed by George ...

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“…[ 11 C]-nicotine is not an ideal ligand, however, because the nAChR-ligand complex rapidly dissociates, its level of nonspecific binding is high, and cerebral blood flow is a major determinant of its accumulation in the brain [Grü nwald et al, 1996;Maziere and Delforge, 1995]. Potential alternatives to radiolabeled nicotine for nuclear medicine imaging nAChRs are high-affinity radiolabeled analogs of the toxin epibatidine Musachio et al, 1997;Patt et al, 1999] or of 3-pyridyl ethers, particularly A-85380 [Abreo et al, 1996]. 5-I-A-85380 ] as well as 2-F-A-85380 [Horti et al, 1996], are halogen substituted 3- [Fujita et al, 2002] and […”

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confidence: 99%

Pharmacology, toxicology, and radiation dosimetry evaluation of [¹²³I]5‐I‐A‐85380, a radioligand for in vivo imaging of cerebral neuronal nicotinic acetylcholine receptors in humans

Vaupel

Tella

Huso

et al. 2003

Drug Development Research

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[123 I]5-I-A-85380, which selectively binds to a4b2 nicotinic acetylcholine receptors, may be a suitable single photon emission computed tomography (SPECT) ligand for imaging nicotinic receptors in the human brain. In a mutagenicity study, 5-I-A-85380 produced positive effects in one of five bacterial strains in the bacterial reverse mutation assay only with metabolic activation. The ED 50 for 5-I-A-85380 to elicit tonicclonic convulsions in mice, 7.1 mmol/kg, i.v., was five times that of nicotine (ED 50 ¼ 1.4 mmol/kg, i.v.). A 2-day acute toxicity study (0.03-150 nmol/kg, i.v.) and a 14-day chronic toxicity study (0.3-30 nmol/kg, s.c.) in mice revealed no evidence of gross pathology or histopathological changes. Biodistribution and dosimetry studies revealed that the urinary bladder wall and the thyroid gland were the critical organs with respect to radiation exposure. In unanesthetized rats, 5-I-A-85380 (5.2-174 nmol/kg, i.v.) and nicotine (20-400 nmol/kg, i.v.) produced similar increases in systolic and diastolic blood pressure, heart rate, and locomotor activity. Doses of 5-I-A-85380 that elevated blood pressure and heart rate by 10% ranged from 5-10 nmol/kg, i.v. The highest doses tested, which produced near maximal increases in blood pressure and heart rate, did not affect the PR, QRS, or QTc intervals of the electrocardiogram. Based on these preclinical data, initial SPECT imaging studies in humans (Fujita et al. [2002] Eur J Nucl Med 29:183-190) used a mass dose of 8.6 pmol/kg [ 123 I]5-I-A-8380, estimated to be 1/580th of the dose that elevates blood pressure and heart rate by 10%. Importantly, no clinical pharmacological effects were observed. Drug Dev.

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Synthesis and in vivo studies of [C-11]N-methylepibatidine: comparison of the stereoisomers

Cited by 29 publications

References 24 publications

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Pharmacology, toxicology, and radiation dosimetry evaluation of [¹²³I]5‐I‐A‐85380, a radioligand for in vivo imaging of cerebral neuronal nicotinic acetylcholine receptors in humans

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Synthesis and in vivo studies of [C-11]N-methylepibatidine: comparison of the stereoisomers

Cited by 29 publications

References 24 publications

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Pharmacology, toxicology, and radiation dosimetry evaluation of [123I]5‐I‐A‐85380, a radioligand for in vivo imaging of cerebral neuronal nicotinic acetylcholine receptors in humans

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Pharmacology, toxicology, and radiation dosimetry evaluation of [¹²³I]5‐I‐A‐85380, a radioligand for in vivo imaging of cerebral neuronal nicotinic acetylcholine receptors in humans